Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-20 are pending and under consideration.
Claim Objections
Claim 8 and 18 are objected to because of the following informalities: “TFN-a” should read “TNF- a”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-20 are unclear with regard to “improving cachexia”. It is not clear if Applicant intends to alleviate symptoms of cachexia or improve the cachexia by increasing the severity of the symptoms. Given the working examples, it would appear the claim would more clearly reflect the invention if it read “ameliorating symptoms of cancer cachexia”. Claims 4-7, and 14-17 recite this phrase in the preamble while further reciting specific symptom improvements. The preamble still remains unclear because the claims do not clarify that the treatment effect correlates to/defines the “improved cachexia”.
Claims 1 and 11 are also unclear in reference to “a culture supernatant”. Use of the term “a” implies that there are multiple supernatants or supernatants with differein compositions, i.e it has been fractionated. Removal of the term “a” or replacing it with “the” is recommended”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5,8-15,18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. (US 2015/0366917 A1) in view of Luft (J Mol Med (2007) 85:783–785), Argiles (John Wiley & Sons, Inc. Med Res Rev, 19, No. 3, 223–248, 1999) and Wei (Journal of Molecular Histology (2020) 51:455–466) as evidenced by Mori (Int. J. Cancer: 67,849-855 (1996), pages 849-855) and Kalluri (Science. 2020 February 07; 367(6478): . doi:10.1126/science.aau6977).
Claims 1 and 11 are each drawn to a method of improving cancer cachexia comprising administering an agent comprising microparticles derived from dental pulp stem cells. Claim 1 requires the agent is a composition comprising the culture supernatant of the dental pulp stem cells while claim 11 requires the composition does not contain the culture supernatant (it is just the microparticles).
Yamamoto et al. (US 2015/0366917 A1) teaches that the inflammatory reaction is a series of processes associated with the elimination of foreign matter and pathogens and the protection and repair of tissue ([0002]). Yamamoto teaches that a culture supernatant of dental pulp stem cells (para 79) from adult or deciduous teeth (para 70; aka SHED) is surprisingly effective at treating intractable inflammatory diseases in mouse models (claims 2 and 12; para 15, 91) and leads to a decrease in expression of proinflammatory cytokines (para 149). With regard to claim 11, which requires no culture supernatant be present and just microparticles from the supernatant be administered, Yamamoto teaches screening fractions to find the components with the ant-inflammatory, treatment activity (para 99). Yamamoto teaches pro-inflammatory cytokines include TNF-a, IL-1b and IL-6 (para 37). Yamamoto lists a number of inflammatory diseases that can be treated by the dental pulp stem cell supernatant, including “cancer and various other diseases involving serious inflammation” (para 91). Yamamoto does not specifically teach cancer cachexia among the list of inflammatory reactions treatable by the DPSC culture supernatant.
However, it was well-known at the time of filing that cancer cachexia is also an inflammatory condition associated with high level of pro-inflammatory cytokines. Luft taught tumor products activate host cells, which initiate a cytokine cascade, primarily through IL-6 and also TNF-a and IL-1, among others (page 784). Likewise, Argiles discusses a balance between pro-inflammatory cytokines (IL-6, TNF-a and IL-1) and anti-inflammatory cytokines (IL-4, IL-10 and IL-12) and that administration of IL-12 has anti-cachectic properties that are associated with a considerable decrease in IL-6 (see page 236, for example; clams 8 and 18) in tumor bearing rats (claims 2 and 12). Similarly, Wei taught SHED (dental pulp stem cells from deciduous teeth) conditioned media and exosomes (claims 3 and 13) obtained therefrom (claim 11; purified and not in culture supernatant), provided therapeutic effects through inhibition of inflammatory cytokines IL-6 and TNF-a. Exosomes are 40-160 nm (claims 10 and 20), as evidenced by Kalluri.
In sum:
Yamamoto-dental pulp stem cell CM to treat inflammatory conditions that result from TNF-a, IL-6 and IL-1
Luft-Cancer cachexia is an inflammatory condition mediated by TNF-a, IL-6 and IL-1
Argiles-reducing IL-6 (with IL-12, for example) has anti-cachectic properties
Wei-dental pulp stem cell CM or exosomes isolated from the CM provide anti-inflammatory effects by lowering IL-6 and TNF-a
Thus, it would have been obvious at the time of filing to use culture supernatant or exosomes of dental pulp stem cells to treat an inflammatory-cytokine related condition as taught by Yamamoto, where the inflammatory-related cytokine condition is cancer cachexia as taught by Luft and Argiles. One would have been motivated to treat the cancer cachexia with the DPSC-conditioned media as Yamamoto taught that conditions caused by elevated IL-6, TNF-a and IL-1 were alleviated by agents in the culture supernatant of DPSCs. Lowering of these same cytokines was also supported in other inflammatory models such as Yamamoto and Wei. One would have been motivated to use only the exosomes as Wei taught anti-inflammatory activity of dental pulp stem cells is present in the exosome fraction, which is more defined and can be used at low concentrations. One would have had a reasonable expectation of success as Argiles taught that lowering the levels of pro-inflammatory cytokines can alleviate cachexia and Yamamoto and Wei taught CM from dental pulp and exosome secreted from dental pulp stem cells have this pro-inflammatory-lowering activity in other inflammatory conditions.
With regard to claims 4-5 and 14-15, Argiles references the study of Mori that lowering IL-6 treated the weight loss in cancerous mice. The weight loss of the vehicle control is show to be 25g to 19g over days 8-17, which would be 2% or more over 14 days since inoculation with cancerous cells.
Conclusion
Claims 6,7,17 and 17 are free of the art. The art fails to teach that dental pulp stem cell conditioned medium or microparticles will treat anemia associated with cancer cachexia. Applicant has submitted Kong, Stem Cell Rev Rep, April 2021, 17:318-331, Abstract only) which shows that DPSC exosomes can mitigate hematopoietic damage following radiation. This, however, does not necessarily correlate to anemia resulting from cytokine toxicity/cancer cachexia.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
